The present invention relates to methods for removing materials utilizing ultra-high frequency acoustical waves, especially as related to surgical procedures.
It is known in the art to use relatively low ultrasonic frequency energy for a wide variety of purposes ranging from communications to polishing. Of particular interest in the art is removal of soft tissue from inaccessible locations.
U.S. Pat. No. 3,589,363 describes a vibratory assembly for removing material from relatively inaccessible regions. This instrument uses a rapidly vibrating knife tip to break down unwanted material into small particles. As the vibrating tip is applied to the material, the region adjacent to the operative site is flooded with fluid. The unwanted material is dispersed into the fluid which, in turn, is removed by suction. Although the vibrating tip will, as a result of this motion, produce an acoustical wave which propagates into the unwanted material, it is recognized in the art that the cutting motion of the tip, and not just the propagation of radiated acoustical energy, produces the desired action and result. (See, for example, C. D. Kelman, xe2x80x9cA Personal Interview Between the Editor and Dr. Charles D. Kelman,xe2x80x9d Boyd""s Highlights of Ophthalmology, Volume XIII, No. 1, 1970-71 Series, p. 43.)
This type of technique, often referred to as phakoemulsification, is perhaps the most widely used xe2x80x9cultrasoundxe2x80x9d technique for removal of cataracts. Since the vibrating tip (or knife) used to cut away the material vibrates at a frequency of 30-40 kHz, it has been termed an xe2x80x9cultrasonicxe2x80x9d method even though the device does not rely upon the propagation of an acoustical wave to cut away tissue. Although effective for what it does, the device is essentially a miniaturized electric knife. Some phako-devices operate at sufficient power levels or have sufficient tip excursions to generate cavitation bubbles. Such bubbles, when they implode, generate sufficient energy to break down material and can, in certain situations, create significant bioeffects.
Another so-called ultrasonic technique has recently been introduced by Baxter-Edwards Healthcare (see Circulation, 89(4):1587-92 (1994)). Here the vibrating knife of phako has been replaced with a large ball tip. This device operates by xe2x80x9cbeatingxe2x80x9d the ball tip against the material to be removed. Material to be removed is broken up by the physical impact of the tool, or by shock waves and cavitation bubbles created by the vibrating tool.
Specifically with respect to methods for treating occluded arteries, balloon angioplasty is the most commonly used method today for recanalizing obstructed arteries. However, this method remains problematic in situations involving complete obstructions, multisegment and multivessel disease, or late restenosis. R. J. Siegel, M.D., describes a variety of techniques being investigated to resolve these problems, but states: xe2x80x9cEach of these technologies also has limitations principally relating to endothelial damage and perforation.xe2x80x9d (Circulation, 78(6):1447 (1988)). In late restenosis, Siegel notes, xe2x80x9c[a]ngioplasty carries an additional risk within the first six months. After the procedure is performed, about 35% of the blockages return although that can be relieved by a repeat angioplasty.xe2x80x9d Id. When blockage re-occurs, secondary surgical intervention is generally necessary immediately.
Ultrasound has also been utilized to remove arterial obstructions. See, for example, Siegel et al., Lancet, pp. 772-74 (Sep. 30, 1989), Ernst et al., Am. J. Cardiol., 68:242-46 (1991), Siegel et al., Circulation, 89(4):1587-92 (1994), DonMicheal et al., U.S. Pat. No. 4,870,953, Guess et al., U.S. Pat. No. 5,069,664, Carter, U.S. Pat. No. 5,269,291, Marcus et al., U.S. Pat. No. 5,295,484, Hashimoto, U.S. Pat. No. 5,307,816, Carter, U.S. Pat. No. 5,362,309, Carter U.S. Pat. No. 5,431,663, and Rosenschein, U.S. Pat. No. 5,524,620. In fact, the highest frequency of acoustical waves disclosed in any of these references as suitable for removing arterial obstructions is 40 MHz (see the Marcus ""484 patent), but, the highest frequency that is actually exemplified in Marcus ""484 is only 14.4 MHz.
These references teach that ultrasound applied to ablate, or otherwise remove, plaque and thrombus operates by means of mechanical action, heat, or cavitation. Furthermore, these references teach that ultrasonic transducers produce a therapeutic effect at a significant distance from the transducer, 10 cm or more, by focusing the ultrasonic waves.
In addition to ultrasound, numerous groups disclose use of lasers to remove arterial plaque using a diversity of wavelengths (colors of light). Lasers in the infrared and visible wavelengths usually ablate by a thermal mechanism, although some may create shock waves or cavitation bubbles that break down tissue.
The excimer laser is successful in excimer laser keratectomy or xe2x80x9claser sculpting of the corneaxe2x80x9d to correct vision. Since this laser operates in the ultraviolet region of the spectrum, it ablates tissue by high energy photons. Certain undesirable side effects that may be encountered in this method include ejection of particles at supersonic velocities, the generation of shock waves, and difficulty in distinguishing healthy from diseased tissue. Also, since the laser operates in the ultraviolet portion of the spectrum, the mutagenic effects of the laser itself and the secondary radiation emitted during the ablation pose possible complications that will not be fully assessed until a long term study is performed.
Another disease state wherein treatment requires destruction of tissue within an inaccessible body cavity is cancer of the prostate. An even greater problem, at least in terms of numbers, is benign prostatic hyperplasia (BPH) for which there are over 400,000 cases per year in the United States alone. For over sixty years, transurethral electroresection of the prostate (TURP) has been the surgical treatment of choice for symptomatic bladder outlet obstruction caused by BPH. For some time, TURP has been considered the xe2x80x9cgold standardxe2x80x9d for comparison when assessing other treatments for this disease.
Since TURP is not without morbidity or serious complications, the urology community has long sought alternate therapies. Currently, laser prostatectomy is proving to be a far better method for the treatment of BPH. In this method, a light fiber directs the energy of the laser (more often an Nd:YAG laser) into the prostate at a 90xc2x0 angle with respect to the catheter where the unwanted material is burned. The destroyed tissue initially stays in place and eventually breaks down and is carried away by the urine over a period of six to twelve weeks. During this recovery period, the patient may experience considerable pain and will not regain normal function for some period of time.
Ultrasound treatment of prostate conditions, including prostate cancer and BPH, has been suggested in the art. See, for example, Watkin et al., Brit. J. Urol., 75(supp. 1):1-8 (1995), Gelet et al., Eur. Urol., 29:174-83 (1996), Schaetzle, U.S. Pat. No. 5,443,069, Chapelon et al., U.S. Pat. No. 5,474,071, Granz et al., U.S. Pat. No. 5,526,815, and Oppelt et al., U.S. Pat. No. 5,624,382. The highest frequency of acoustical waves disclosed in these articles is 9.8 MHz in the Watkin article. In the procedures described in this group of references, the ablation of tissue is accomplished through heating or cavitation caused by the ultrasound energy. When the ultrasonic waves are focused, such effects can occur at a significant distance from the transducer, for example, 10 cm or more.
The relatively low ultrasonic frequencies disclosed in the art travel much farther from the transducer through the tissue before being substantially attenuated than is desirable in many applications. In addition, during passage through tissue, the energy of low-frequency ultrasound is converted to heat, physical forces, and acoustical pressures over an undesirably large area, as opposed to confining the energy delivery to the unwanted material or tissue. Furthermore, because of the undesirable time-dependent spread of effects beyond the target area, previous investigators have often used continuous ultrasonic frequency waves in an attempt to ablate the target tissue in as short a time period as possible.
In addition to the use of ultrasound to break down tissues physically, ultrasound has been used to kill tissues by the generation of heat. This use of ultrasound to kill or harm cells at a distance from the transducer is commonly referred to as thermotherapy or hyperthermia. See, for example, ter Haar, Ultrasound in Med. and Biol., 21(9):1089-100 (1995), Pounds, U.S. Pat. No. 4,441,486, Hall et al., U.S. Pat. No. 5,460,595, Unger et al., U.S. Pat. No. 5,558,092, and Chapelon et al., U.S. Pat. No. 5,601,526. Although these references disclose a wide variety of frequencies at which the ultrasound energy is applied to the patient, all of them work by focusing the energy at a point distant from the transducer within the body of the patient. Because the majority of the ultrasound energy impinges upon the focal point, relatively little heating occurs in the tissues between the transducer and the focal point, while the temperature at the focal point may be elevated significantly, causing death to cells and tissues therein.
Ultrasound has also been used to image tissues and non-living structures internally. It is known in the art to use ultrasound at a variety of frequencies, from about 1 MHz to about 600 MHz, for imaging and diagnostic (but not treatment) purposes. See, for example, Harland et al., Brit. J. Dermat., 128:525-32 (1993), Nielsen et al., Ultrasound in Med. and Biol., 19(9):717-25 (1993), Aslanides et al., Brit. J. Ophth., 79:972-76 (1995), Tong et al., Ultrasound in Med. and Biol., 23(6):735-46 (1996), Gniadecka, J. Am. Acad. Derm., 35(1): 37-41 (1996), Chandraratna et al., Am. Heart J., 133:364-68 (1997), Thomas, III et al., U.S. Pat. No. 4,911,170, and Bom et al., U.S. Pat. No. 5,176,141. The purpose of the devices and procedures disclosed in these references is diagnosis. As such, these devices and procedures are not intended to ablate or otherwise remove the target tissues of the patient, but only to provide images thereof. The equipment used in diagnostic imaging operates well at Spatial Peak Temporal Averaged Intensities (I(SPTA)) below or about 100 mW/cm2. In general, significant damage to tissue, such as results in irreversible biologic effects, requires use of I(SPTA) significantly greater than 100 mW/cm2.
U.S. Pat. No. 3,941,122 describes experiments demonstrating the successful liquefaction of lens, cataract, vitreous, and vitreous membrane in excised human, cattle, baboon, and rabbit material using ultra-high frequency ultrasound, but dissolution of other types of tissue or materials is not disclosed therein.
With respect to non-medical uses of ultrasound, vibratory assemblies for cutting material have been used for some time in a wide number of applications. One such apparatus employs a slurry of abrasive particles in conjunction with an ultrasonically vibrating tool, as described, for example, in U.S. Pat. No. 2,580,716. The vibratory energy imparted to the abrasive particles in the slurry hurls them with tremendous acceleration against the surface to be cut, thereby literally chipping away the material. This technique has been applied with great success, particularly in the case of industrial machine tools. Such vibratory assemblies, however, are ineffective for cutting yielding materials and also require a fairly open site so that the interposition of the slurry between the vibrating tool tip and the work surface can be maintained.
In view of the above, it can also be seen that new and better methods and devices are needed for using ultrasonic acoustical waves for surgical procedures. It would be especially advantageous to provide a teclmique that is tissue specific, highly selective, and very localized for use in such surgical procedures as causing the total disintegration of atherosclerotic build-up, and like materials, without damaging healthy surrounding tissue or producing suspensions of particularized material of such size that they must be artificially transported from the surgical site.
In the present invention, methods and devices are provided for utilizing energy from ultra-high frequency acoustical waves to remove unwanted material with specificity from a highly localized site of action, such as a medical treatment site at an inaccessible location within the body.
In one embodiment of the invention, there are provided methods for causing dissolution of unwanted solid or semi-solid material comprising forming ultrasonic acoustical waves having a frequency greater than 50 MHz and a sufficient amplitude to cause dissolution of the unwanted material without substantial damage to surrounding material, and applying the waves to the unwanted material via a zone of acoustical mismatch to cause said dissolution thereto. This effect is enhanced if the generated waves encounter a layer of highly elastic material located at the surface of the unwanted material. Generally, the acoustical waves used in practice of the invention have a Spatial Peak Temporal Averaged Intensity (I(SPTA)) greater than 100 mW/cm2 but provide energy below the cavitation threshold in water at atmospheric pressure.
Such ultra-high frequency sonic energy is highly attenuated over a short distance due to various energy transfer mechanisms at the molecular and macromolecular levels. Therefore, it is preferred to place the ultrasonic transducer in actual contact with the surface of the material whose disruption and dissolution is desired. It is believed that ultra-high frequency energy is absorbed in the immediate region to which it is applied and effectively breaks down tissue because the frequency of such acoustical waves is extremely close to the average resonant frequency of cell structures and macromolecules (whose dimensions are in the same size range (i.e. about 15 xcexcm) as the wavelength associated with the ultra-high frequency ultrasound utilized in the invention methods and devices). Thus, such tissue structures as cells, and components thereof, are put into a vibrational phase resulting in various types of shear and torsional stresses that cause intracellular and/or molecular bonds to break apart, releasing individual cells or clumps of cells, etc. by breaking down cell membranes.
In addition, because the attenuation of ultra high frequency acoustical waves in tissue takes place over a distance less than 1 mm, a radiation pressure is created that aids the dissolution process. An oscillating radiation force that creates alternating compression and rarifaction causes structures to vibrate longitudinally. This effect is directly proportional to the rate of attenuation of the waves.
To enhance the shear stresses within unwanted material, in the invention methods, the acoustical waves applied to the unwanted soft tissue have a significant transverse wave component in addition to the longitudinal wave component, such as results, in part, from passage of the wave through a boundary between substances of unmatched elastic modulus. For example, it has been discovered that the capacity of ultra-high frequency acoustical waves to dissolve material, such as soft bodily tissue, is enhanced if the acoustical waves are not applied via an xe2x80x9cacoustical matching layer.xe2x80x9d In this situation, there is an impedance mismatch that inhibits propagation of the waves into the unwanted material and contributes to formation of a transverse xe2x80x9cshearxe2x80x9d component in the propagating wave, thereby enhancing the destructive capacity of the waves as well as the rapid attenuation of the waves within the unwanted material. Mode conversion into a shear wave component can take place even though the medium to be dissolved, such as tissue, will not support a shear stress. In this case, the shear wave is very rapidly attenuated, further localizing the effect of the shear component in accomplishing dissolution of the material.
It has also been discovered that the transverse component of the acoustical wave can be further enhanced if it is applied through an interposing layer of highly elastic material about 1 wavelength in thickness at the operating frequency. Such a layer, in effect, amplifies the waves produced by the transducer. This amplifying effect is greatest if the layer of highly elastic material is fixedly attached to the active face of the transducer.
In the invention methods and devices, ultra-high frequency acoustical waves are delivered to unwanted material in a controllable, localized area, preferably by direct contact with the active face (i.e., working surface) of the ultrasonic transducer, for example, in a repeated rubbing motion (i.e., by erasion). Since this invention, furthermore, does not depend upon the material being battered by acoustical waves or a mechanical structure, it has been discovered that applying ultra-high frequency energy to the unwanted material in pulses, rather than as a continuous wave, may actually reduce the time required to dissolve tissue structures; however continuous wave application is also effective. In pulsed mode operation, for example in pulses of about 10 to about 100 wavelengths in duration, substantially higher wave amplitudes, but lower energy densities, can be applied to the unwanted material with the assurance that any high-frequency vibratory mode imparted to the unwanted material by the acoustical waves will also be absorbed within the localized area of the target tissue. Pulsed mode operation also prevents build-up of heat and reduces the likelihood of cavitation in the target tissue.
For example, at frequencies in the range from 50 to 150 MHz, dissolution only occurs in close proximity to the face of the transducer with the actual distance depending upon the elastic and acoustical properties of the propagating medium (e.g. the unwanted material). Adverse rises in temperature are also prevented, preferably by selecting a pulsed mode of operation (though in some particular instances continuous wave operation and/or cooling may be necessary), such that coagulation of tissue and other disadvantageous side-effects accompanying adverse temperature rises can be avoided.
Whereas relatively low frequency ultrasonic devices break apart unwanted material by mechanical impact or cutting action, the present technique uses a radiated propagating wave of ultra-high frequency ultrasonic energy, preferably in short pulses, to disrupt or dissolve unwanted material into its cellular, subcellular, and/or molecular components in a highly controlled and localized manner.
For many applications, frequencies on the order of 90 to 100 MHz and higher have been shown to be particularly useful in the practice of the invention. The attenuation of ultrasound in soft tissue at such high MHz ranges has been determined to be approximately proportional to the 1.3 power of frequency. Attenuation is also influenced by the acoustical and elastic properties of the unwanted material to which it is applied. For example, acoustical attenuation in tissue is high compared to most materials, about 1 dB/cm/MHz. It follows that if a 100 MHz sound wave is just intense enough to dissolve material at the surface of the transducer, the wave need propagate only a few wavelengths for the effects of attenuation to reduce the intensity of the wave (i.e., to what can be considered a safe level). In tissue, such attenuation occurs within about 0.3 mm and in some materials total attenuation of the acoustical waves occurs within about 1 to 10 wavelengths. This indicates that ultrasound having a frequency in the 100 MHz range can be used to dissolve unwanted material in a very localized region without deleteriously affecting the surrounding material. By contrast, acoustical waves at 1 MHz travel about 3 cm before attenuation reduces its power by one half.
Similarly, wavelength helps to determine the type of destructive forces that operate in target material and the size of the particles generated. When the wavelength of sound is relatively long, cavitation and/or gross mechanical motion produce the break-tip of unwanted material. Such a situation certainly exists if the frequency of the sound is around 40 kHz or below, as in certain prior-art systems before-discussed. When, however, the wavelength of sound is very much smaller, as it is at 100 MHz, the mechanical energy associated with the propagating sound wave breaks down the unwanted material into cellular, macromolecular, and/or molecular components. When used surgically, this process is also described as one of cytolysis because the sound energy disrupts tissue into a subcellular or cellular collection of particles. The depth of material breakdown as measured from the surface of the material to be treated is frequency dependent and the unwanted material can be dissolved to a microscopic level of arbitrarily desired dimensions by selecting the appropriate frequency. These unique features are not possible with prior art techniques that depend on a vibrating mechanical tool, an abrasive slurry, cavitation phenomena, and/or the focusing of acoustical energy, and the like.
It has been discovered that atherosclerotic plaque, thrombus and other buildup, such as fat, can be dissolved by applying 100 MHz transducers to fresh samples according to the invention method. Applicant has employed transducers driven at a resonance frequency by a gated sine wave some 64 microseconds in duration with a pulse repetition rate of one every 400 microseconds. Although absolute power measurements were not made (in fact, it is extremely difficult to make such measurements at these frequencies, especially when operating in a pulse mode), it was determined, using a small thermocouple, that no rise in temperature occurred when the tissue was treated by ultrasound. Examining the ultrasound irradiation process under optical microscopy, no indication of cavitation was noted. Thus, it is concluded that the mechanism causing the tissue to be removed is non-thermal and purely mechanical, with power levels well below the cavitation threshold.
Further, experimentation has led to the theory that the longitudinal wave produced by the transducer undergoes a partial mode conversion at the tissue interface, thereby producing a transverse wave component that shears the tissue at the microscopic level, a thin layer at a time. This effect is aided by a high impedance caused by a large mismatch in elastic properties, such as elastic modulus, between the transducer and the tissue. The longitudinal component of the acoustical waves also plays an important role in disrupting materials by producing the acoustical equivalent of Newton""s Rings on the surface of the transducer. Newton""s Rings represent rings of high and low pressure regions which radiate outward from a central point across the active face of the transducer. These rings have the effect of producing a further shearing action at the boundary between the transducer and the tissue. Such a process insures that the particle size of the removed tissue is sufficiently small to be easily carried away by the blood or other bodily fluids. Microscopic observation of the products of ultrasonic irradiation by the invention methods and apparatus have confirmed that the particle sizes are no larger than several microns in dimension.
Accordingly, it is contemplated that the invention methods and apparatus can be utilized in a number of surgical and non-surgical applications. For example, the invention methods and apparatus can be utilized for in vivo treatment of atherosclerotic build-up, prostate disorders, cancers, orthopedic and cosmetic surgery, various types of orthopedic surgery, including atheroscopic surgery, and the like. At the microscopic biomedical level, a microscopic transducer operating at about 1 GHz could produce changes at the micron level and would permit xe2x80x9csurgeryxe2x80x9d on cells and cellular structures. At even higher frequencies of about 100 GHz to about 1 THz, xe2x80x9csurgeryxe2x80x9d could be undertaken at the molecular level. For example, chains of DNA could be cut, moved to new locations on the chain, or replaced by alternate sections or sequences. The present invention is also useful in a wide variety of non-surgical applications, including industrial processes wherein the apparatus is used as a cutting tool wherein materials are desired to be selectively destroyed in a very localized region.
In another embodiment of the invention, there are provided novel ultra-high frequency transducers for converting electrical energy to ultrahigh frequency acoustical waves, said transducer comprising a substrate, a piezoelectric element mounted on the substrate and adapted to generate acoustical waves having at least one resonant frequency in the range from about 50 MHz to about 100 GHz, electrodes attached to opposite faces of the piezoelectric element for applying an alternating voltage across the element at the resonant frequency, and a layer of highly elastic material attached to a face of the element. The layer of highly elastic material is generally of uniform thickness and is attached to the active face of the piezoelectric element (i.e., from which sound propagates toward the unwanted material) for the purpose of increasing the amplitude of the acoustical waves generated by application of an alternating voltage across the element, but without a corresponding increase in the maximum value of the voltage applied to the element. Therefore, at a given voltage across the piezoelectric element from the power source, the ultra-high frequency acoustical waves produced by the invention transducer have substantially increased amplitude compared to those produced by such a piezoelectric element in the absence of the highly elastic layer. In a preferred embodiment, the invention transducer is an improvement to the type of transducer known in the art to form a xe2x80x9cplane piston source.xe2x80x9d
Opposite faces of the piezoelectric element(s) have an electrode attached thereto or are otherwise in contact with a power source for applying a voltage across the expansion axis of the element. Electrical leads can be attached to the electrodes, for example by bonding with an electrically conductive solder, to deliver electrical impulses provided by an externally located power source. One or both of the electrodes can be in the form of a thin layer of a metallic substance, such as gold, attached to, or deposited on, the face of the piezoelectric element.
In another embodiment, there is provided apparatus comprising, in combination, an ultra-high frequency energy source adapted to provide energy to an invention transducer, as described above, wherein the transducer is emplaced at the open tip of a casing, wand, or catheter from which the acoustical waves generated by the transducer radiate forward along the axis of the catheter. The catheter is provided with a proximal handle to enable application of the radiating tip to a juxtaposed region of material whose dissolution is desired. For example, at least one lumen of the catheter can be adapted to receive a guidewire channeled through the lumen, which guidewire is connected to the proximal handle or guidewire port. The extension of the guidewire through the distal tip of the catheter is used to manipulate passage of the catheter through the lumen of an artery, or other bodily lumen, as is known in the art. Alternatively, to facilitate passage of the catheter through a curved body lumen, such as the branching of an artery, the substrate is in the shape of a hollow truncated cone with the modified washer-shaped piezoelectric element mounted distally at the end of the cone having the smaller diameter.
Apparatus designed for applying ultrasonic energy used in diagnostic imaging typically applies the ultrasonic energy to the target tissue via an interposed acoustical matching layer (e.g., a layer coating the wand), which layer is selected to maximize propagation of the sonic waves deep into the tissue or other material to be imaged. However, the invention apparatus omits such an acoustical matching layer at the tip of the casing or wand that houses the transducer to assure rapid attenuation of the acoustical waves in the target material, to increase the amplitude of the mechanical wave propagated into the unwanted material, and to enhance production of a shearing force at the interface between the transducer and the unwanted material. Instead of the acoustical matching layer, the invention apparatus comprises an ultra-high frequency transducer having a piezoelectric element with a layer of highly elastic material attached to the active face and mounted at the radiating tip of the casing or wand that houses the transducer. Therefore, when the transducer is placed in contact with the material to be dissolved, as in the currently preferred embodiment, it is the layer of highly elastic material affixed to the element that actually contacts the surface of the unwanted material. Due to the great mismatch in the elastic properties between the unwanted material and the highly elastic layer, mode conversion to a shear wave component is enhanced at the interface with the material to be treated.
An object of the invention, accordingly, is to provide a new and improved process and apparatus for employing ultra-high frequency ultrasound acoustical wave energy at very high amplitude, preferably in short evenly spaced pulses, to dissolve materials, particularly semi-solid and solid materials, such as soft tissue, including atherosclerotic build-up, and the like, to effect highly controllable, selective, and localized ultrasonic tissue disruption, dissolution, and/or erasion without substantial damage to surrounding material.
The novel process and apparatus are particularly adapted to safe removal of atherosclerotic material and other unwanted tissues from the human or animal body at inaccessible locations with the above novel results.
An additional object is to provide a method for selectively disrupting and removing unwanted solid and semi-solid materials of a wide variety of types, such as in industrial and materials science applications, without the use of abrasive substances.
In therapeutic applications, the invention provides the advantage of selectively removing unwanted tissue in a minimally invasive manner without substantial damage to surrounding tissues and structures. This technology has the potential for literally revolutionizing treatment of cardiovascular disease and numerous other fields of surgery and medicine, while significantly reducing the cost as compared to that of conventional procedures.
Other and further objects will be explained hereinafter and are more particularly defined in the appended claims.